Levothyroxine Sodium is a synthetic form of thyroid hormone Thyroxine, which is secreted from follicular cells of thyroid gland. Levothyroxine is ideally used for the treatment of thyroid hormone deficiencies such as hypothyroidism. Due to its ability to lower thyroid-stimulating hormone, Levothyroxine is also used in the treatment of goiter and also to prevent the recurrence of thyroid cancer.
Levothyroxine Sodium has the following chemical structure.

For the preparation of Levothyroxine Sodium several methods have been known. U.S. Pat. No. 2,889,363 demonstrates the use of animal natural sources as starting material for the preparation of thyroxine while U.S. Pat. No. 2,889,364 discloses an enzymatic or bio-mimetic method of synthesis for levothyroxine.
The invention disclosed in U.S. Pat. No. 2,889,363 provides a process for the production of esters of N-acylthyroxine with a substantial reduction in the time period and involves digestive coupling reactions in which alkyl esters of N-acyldiidotyrosine yield alkyl esters of N-acylthyroxine in a greatly reduced time in the presence of optimal catalyst concentration, pH range and alcohol concentration. This prior art further involves a process for production of thyroxine by incubating alkyl esters of N-acyldiidotyrosine derived from lower alkanols and lower alkanoic acids in aqueous solution of ethanol (70%) of pH of 9.5-10.5 and in the presence of between 1.5 and 5% by weight of a manganese containing catalyst while passing substantially pure oxygen through the solution and while maintaining the temperature in the range of 25° C. to 78° C., and hydrolytically removing acyl and ester substituents from the ester of N-acylthyroxine obtained from the incubation step.
PCT publication No. WO 1996011904 discloses further improvements to a six stage process for production of sodium 1-thyroxine from 1-tyrosine as described in U.S. Pat. No. 2,889,363 and U.S. Pat. No. 2,889,364. These improvements comprise the oxidative coupling of a diiodo-1-tyrosine to form a biphenyl ether derivative, catalysed by a manganese salt in which the amine and acid functionality of the diiodo-1-tyrosine have been protected by suitable protecting groups, characterised in that the reaction is performed at a pressure of about 20 atmospheres in the presence of an organic amine additive using a gaseous oxidant comprising oxygen and optionally an inert diluent. The process optionally further comprises acid hydrolysis of the biphenyl ether derivative with hydrochloric acid to form 1-thyroxine hydrochloride salt and generation of sodium-1-thyroxine from the 1-thyroxine hydrochloride salt.
PCT publication number WO2009136249 provides a process for the preparation of levothyroxine sodium and comprises the steps of: iodinating 3, 5-diiodothyronine to obtain crude levothyroxine, followed by its conversion to disodium salt and acidifying the disodium salt to give pure levothyroxine. The purified levothyroxine is converted to levothyroxine sodium having reduced level of impurities. Levothyroxine sodium obtained by this invention is substantially free from d-enantiomer of thyroxine/3, 5-Diiodothyronine impurity. The process also reports the d-enantiomer of thyroxine/3, 5-Diiodothyronine levels below the limit of detection and liothyronine impurity below 0.5% wt/wt. The end product derived from this process is also free from coloured impurities.
Many patent and non-patent literature describe the use of an intermediate called Bis (p-anisyl)iodonium bromide in the preparation of Levothyroxine sodium. Hillmann (Z. Naturforch 1956; 11b:424-425) describes a process for the assembly of the biphenyl-ether system present in Levothyroxine, wherein a key coupling reaction is initiated between N-Acetyl 3,5-diiodo-L-tyrosine ethyl ester, derived from the stepwise protective conversion of amine as amide and acid as ester of 3,5 diido-L-tyrosine, and Bis (p-anisyl)iodonium bromide in the presence of copper metal or powder as a catalyst to afford (S)—N-acetyl-3,5-diiodo-4-p-methoxyphenoxyphenylalanine ethyl ester, with 87% yield. All the three protective groups in (S)—N-acetyl-3,5-diiodo-4-p-methoxyphenoxyphenylalanine ethyl ester, viz. acetamide, methyl ether, ethyl ester were cleaved using a mixture of Hydroiodic acid and Hydrobromic acid to give 3,5-Diiodothyronine. 3,5-Diiodothyronine on subsequent iodination with iodine gave L-thyroxine of an yield that corresponds to 92%.
The use of Bis (p-anisyl)iodonium bromide in the synthesis of thyroxine leads to the formation of an impurities called monobromo triiodo tyrosine and dibromo triiodo tyrosine which may be categorized as “Genotoxic impurities” based on the structure alerts. The levothyroxine compositions thus prepared are not generally preferred due to their genotoxic impurity content associated with purified Levothyroxine.
The aforesaid prior art processes cannot be considered for industrial scale preparation in view of their shortcomings such as less yield of the product, high expenses involved, pressure reactions which are less feasible for commercialization of the product, more number of reaction steps, cycle time and concerns about the purity of the endproduct. Hence there is a long-felt need for the development of an improved process that circumvents the above disadvantages and provides an industrially feasible, cost effective process involving the use of commercially available, simple raw materials in the process. At the same time it is also required that the process or technology developed should be easily adaptable for multikilo manufacturing plants for scaling-up the most demanding API product, Levothyroxine sodium at a very cheap cost, compared to the current import costs of the material and contemporary technologies in vogue.